Serotonin (5-HT) signaling has been a major focus of drug development targeting seizures in Dravet syndrome (DS) in recent years. For example, the community recently saw the FDA-approval of Fintepla (fenfluramine) as an adjunctive (add-on) therapy for DS. Fenfluramine had been a known anti-epileptic agent since the 1980’s, particularly utilized in Europe, but its marketing as a weight loss drug used at high concentrations for obesity in adults had led to market withdrawal in the late 1990’s because of concerns over adverse cardiac side effects (1). However, recent clinical trials indicated high efficacy of low-dose fenfluramine to reduce seizures in DS without indication of any serious cardiac issues (1). Now other 5-HT modulating compounds are under pre-clinical investigation or entering clinical trials in patients with DS, including the drug lorcaserin.
In 2017, the Baraban lab demonstrated several 5-HT modulating compounds could reduce seizures in a zebrafish model of DS, including clemizole and lorcaserin (2). At the time, lorcaserin was FDA-approved as a weight loss drug and being marketed by Eisai under the name Belviq. The market-availability of Belviq (lorcaserin) led researchers to commence a small study of “off-label” use of Belviq in patients with DS (n=5) to assess impacts on seizure frequency (2). Although, as is often the case in DS, the individual impacts on seizure frequency were variable, all patients experienced some degree of decreased seizure activity (2). In a follow-up study in 2018, the efficacy of lorcaserin to reduce seizures was again confirmed in 35 patients with childhood onset epilepsy (3). Patients with DS (n=20) and Lennox-Gastaut syndrome (n=9) saw the most benefits with 43% and 50% reductions in seizure activity. Side effects were generally mild, most commonly including decreased appetite and weight loss. These findings led to some patients with DS using Belviq “off-label” when other medications were not providing adequate seizure control.
Unfortunately, in early 2020, Belviq (lorcaserin) was removed from the market by the FDA after patients (adults taking the medicine for weight-loss) were found to have a slightly increased risk of cancer (0.6% higher incidence) than individuals taking a placebo. Eisai, the manufacturer of Belviq, worked with the FDA and the DS community to continue the availability of Belviq to patients with DS already utilizing the medication for seizure control under an expanded access program. Now, Eisai has launched a Phase 3 clinical trial called Momentum I to study the efficacy of lorcaserin as an adjuctive (add-on) treatment in DS to reduce seizure frequency. This quadruple-blinded, placebo-control study is seeking to enroll 58 participants in a 14-week core study, with the potential for participants to enter an additional 12-week open-label extension phase following completion of the core study. Enrollment is now open and study sites are still being added. Find more information on the Momentum I study for lorcaserin at clinicaltrials.gov and read the press release from Eisai here.
Given the previous work suggesting efficacy of lorcaserin to reduce seizure burden in small groups of patients, in combination with the strong evidence that 5-HT modulating drugs are efficacious in animal models of DS and larger groups of patients (1-4), we are hopeful that lorcaserin will add to the list of medication options for patients and families with DS seeking better seizure control with fewer side effects.
You can additionally find more information about another 5-HT modulating drug mentioned above, clemizole, entering clinical trials from Epygenix and Greenlight Clinical here or at clinicaltrials.gov.
- Lagae L, Sullivan J, Knupp K, Laux L, Polster T, Nikanorova M, Devinsky O, Cross JH, Guerrini R, Talwar D, Miller I, Farfel G, Galer BS, Gammaitoni A, Mistry A, Morrison G, Lock M, Agarwal A, Lai WW, Ceulemans B, FAiRE DS Study Group. (2019) Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: a randomized, double-blind, placebo-controlled trial. The Lancet. 394 (10216): 2243-2254.
- Griffin A, Hamling KR, Knupp K, Hong S, Lee LP, Baraban SC. (2017) Clemizole and modulators of serotonin signaling suppress seizures in Dravet syndrome. Brain 140: 669-683.
- Tolete P, Knupp K, Karlovich M, DeCarlo E, Bluvstein J, Conway E, Friedman D, Dugan P, Devinsky O. (2018) Lorcaserin therapy for severe epilepsy of childhood onset: A case series. Neurology 91(18): 837-839.
- Griffin AL, Jaishankar P, Grandjean JM, Olson SH, Renslo AR, Baraban SC. (2019) Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome. Brain Communications. doi:10.1093/braincomms/fcz008